Conventionally, cellulose particles such as crystalline cellulose and powdered cellulose have been widely used as an excipient to prepare molded products containing an active ingredient in the field of pharmaceutical, food and other chemical industries. Good compactability, flowability and disintegration property are required for these cellulose particles.
Patent Document 1 describes porous cellulose particles having crystal form I, pores with a pore size of 0.1 μm or more and a porosity of 20% or more and a fraction of not less than 350 mesh by 90 wt % or more (corresponding to Comparative Example 6 of the present application) obtained by mixing cellulose particles with a third ingredient such as a crystalline material insoluble or poorly soluble in water and soluble in an organic solvent, granulating and drying using them or using an aqueous solution of water-soluble organic solvent, subsequently extracting and removing the third ingredient with an organic solvent. Since the porous cellulose particles disclosed in this document form a film-like dense and strong cellulose wall structure formed of primary cellulose particles compacted so uniformly and continuously such that the borders of the particles are indistinct, they completely different from the porous cellulose aggregate of the present invention in the particle structure. Although the cellulose particles according to Patent Document 1 are excellent in flowability, the dense and continuous cellulose wall has little water permeability and therefore they do not disintegrate in water, which may pose a problem in quickly releasing the active ingredient. In addition, the cellulose particles according to Patent Document 1 are poor in plastic deformation properties when the cellulose is compressed, the compactability thereof is insufficient, and the use of an organic solvent and a third ingredient such as a crystalline material soluble in an organic solvent in the production process not only increases the production cost but also may deactivate the active ingredient, and it is not sufficient to be stably used as an excipient.
Patent Document 2 describes porous fine cellulose particles having crystal form I, a porous structure with a specific surface area of 20 m2/g or more and a pore volume by pores having a diameter not less than 0.01 μm of 0.3 cm3/g or more and an average particle size of at most 100 μm (corresponding to Comparative Example 7 of the present application) obtained by granulating and drying particulate natural cellulose dispersed in an organic solvent by spray-drying method. These fine cellulose particles also have the above-mentioned cellulose wall structure, and are totally different from porous cellulose aggregate of the present invention in the particle structure. Furthermore, although the pore volume of the cellulose particle of Patent Document 2 is large in itself, water is hard to permeate into the particle because the particle structure is different from the porous cellulose aggregate of the present invention, and therefore it has a problem of poor disintegration property. In addition, this porous cellulose aggregate particle uses an organic solvent in the production process, which not only increases production cost but also results in too large specific surface area and may promote mutual action between the active ingredient and water and deactivate the active ingredient and therefore it was not sufficient to be stably used as an excipient.
Patent Document 3 describes a cellulose powder having an average polymerization degree of 150-375, an apparent specific volume of 1.84-8.92 cm3/g and a particle size of 300 μm or less (corresponding to Comparative Example 8 of the present application) as a cellulose powder having a good compactability and disintegration property.
Patent Document 4 describes a microcrystalline cellulose aggregate having an average polymerization degree of 60-375, an apparent specific volume of 1.6-3.1 cm3/g, an apparent tapping specific volume of 1.4 cm3/g or more and a repose angle of 35-42° and containing 2-80 wt % of ingredients of not less than 200 mesh (corresponding to Comparative Example 9 of the present application) as a cellulose powder having a good compactability and disintegration property.
The cellulose powders obtained by Examples described in these Patent Documents have small pore volume within a particle according to pore distribution measurement obtained by mercury porosimetry, and it is completely different from the pore structure which has been intentionally formed as the present invention. On this account, these cellulose powders have a small specific surface area as small as 0.6-1.2 m2/g and low compression compactability. These Patent Documents disclose controlling compactability, flowability and disintegration property of the cellulose particles by adjusting the value of apparent specific volume but there was a problem that when the apparent specific volume was in a relatively small range of 2.0-2.9 cm3/g, compactability was not satisfactory although flowability and disintegration property could be excellent whereas when the apparent specific volume was in a slightly increased range of 3.0-3.2 cm3/g, flowability and disintegration property deteriorated although compactability was excellent.
Patent Document 5 describes β-1,4-glucan powder having an average particle size of 30 μm at most and a specific surface area of 1.3 m3/g (corresponding to Comparative Example 1 of the present application) as a cellulose powder having a good compactability. The β-1,4-glucan powder described in the document does not have secondary aggregate structure and there are contained individual primary particles independently. Although this glucan powder had a good compactability, it had a problem that it was inferior in disintegration property. In addition, it was poor in flowability because the average particle size was small.
Patent Document 6 describes, as a cellulose powder having a good compactability and disintegration property, a cellulose powder having an average polymerization degree of 100-375, acetic acid retention of 280% or more, a value of 0.85-0.90 and b value of 0.05-0.10 in Kawakita equation (P·V0/(V0−V)=1/a·b+P/a), an apparent specific volume of 4.0-6.0 cm3/g and an average particle size of 30-120 μm and containing substantially no particles of 355 μm or more (corresponding to Comparative Example 10 of the present application) obtained by hydrating a cellulose base material. The cellulose powders obtained by Examples in this document have also small pore volume within a particle according to pore distribution measurement obtained by mercury porosimetry, and it is completely different from the pore structure which has been intentionally formed as the present invention. There is a description that cellulose powder of Patent Document 6 is excellent in compression compactability and disintegration property, but when the repose angle of Examples having the most excellent balance as specifically disclosed was measured, it exceeded 55° and flowability was not sufficiently satisfied, and therefore there was a problem that the variation index of tablet weight became large in a formulation containing a large amount of active ingredient which was poor in flowability, and the homogeneity of the content of pharmacological agents was affected. In addition, when the cellulose powder of this document was molded under high pressure, high hardness could be provided but there arose a problem of delayed degradation since it had no intentionally formed pores within a particle and had little water permeability into the inside of the particle.
Patent Document 7 describes a crystalline cellulose characterized in that it has an average polymerization degree of 100-375, contains particles which pass a 75-μm screen but remain on a 38-μm screen in an amount of 70 wt % or more of the total weight and has an average ratio of the longer axis to the minor axis of 2.0 or more (corresponding to Comparative Example 11 of the present application) as a cellulose powder having a good compactability, flowability and disintegration property.
Patent Document 8 describes a cellulose powder having an average polymerization degree of 150-450, an average L/D (longer axis/minor axis ratio) ratio of 2.0-4.5 for particles of 75 μm or less, an average particle size of 20-250 μm, an apparent specific volume of 4.0-7.0 cm3/g, a repose angle of 54° or less and a specific surface area of 0.5-4 m2/g (corresponding to Comparative Examples 2 and 3 of the present application) as a cellulose powder having a good compactability, disintegration property and flowability.
The cellulose powders described in these documents have also small pore volume within a particle measured by mercury porosimetry as mentioned above, and they are completely different from the pore structure which has been intentionally formed as the present invention. The cellulose powders described in these documents provide molded products with high hardness by making the shape of a particle elongated. However, since they have elongated shape, the apparent specific volume increases, and the more compactability increases, the more flowability decreases. When the repose angle was measured for the cellulose powders of Examples described in these documents having the most excellent flowability, it was 44°, when continuous forming at a high rate in a formulation containing a large amount of active ingredient which was poor in flowability, the variation index of tablet weight became large and the homogeneity of the content of pharmacological agents was affected. Therefore the flowability was not satisfied. Furthermore, when the cellulose powders described in these documents were molded under high pressure, high hardness could be provided but there arose a problem of delayed degradation since they had no intentionally formed pores within a particle and had little water permeability into the inside of the particle.
Although the cellulose powders described in these Patent Documents 5-8 provide a sufficient compactability as far as the apparent specific volume is in a range of 2.3-6.4 cm3/g, they had a problem that flowability and disintegration property deteriorate.
Patent Document 9 describes pharmaceutically inert spherical seed core containing 10-70% of a crystalline cellulose having an average polymerization degree of 60-375 and 10-90% of a water-soluble additive as a cellulose powder having a good flowability. Patent Document 10 describes pharmaceutically inert spherical nucleus containing 50% or more of a crystalline cellulose having a water absorption power of 0.5-1.5 ml/g, a sphericity of 0.7 or more, an apparent tapping specific volume of 0.65 g/ml or more, an abrasion degree of 1% or less and an average polymerization degree of 60-375 (corresponding to Comparative Example 12 of the present application) obtained by kneading a powder containing 50% or more of a crystalline cellulose with distilled water in a mixing and stirring granulating machine while mixing. Patent Document 11 describes a microcrystalline cellulose powder having a nondense density of at least 0.4 g/cm3 (2.5 cm3/g in terms of apparent specific volume), a spherical shape, an average particle size of 5-35 μm and a smooth surface obtained by mechanically reducing the particle size of hydrolyzed cellulose particles and performing spray drying. Patent Document 12 describes cellulose particles containing 10% or more of a crystalline cellulose having an average polymerization degree of 60-350, an apparent tapping specific volume of 0.60-0.95 g/ml, a sphericity of 0.7 or more, a shape factor of 1.10-1.50 and an average particle size of 10-400 μm (corresponding to Comparative Example 13 of the present application) obtained by hydrolyzing a cellulose base material so that the average polymerization degree may be 60-350 and then mechanically grinding it until the average particle size may be 15 μm and drying a dispersion containing the resulted crystalline cellulose in the form of droplets.
The cellulose particles described in these publications do not take secondary aggregate structures and the cellulose particles obtained by the method described in these patent documents have an apparent specific volume of 2.5 cm3/g or less, a shape near a sphere and an excellent flowability but they are inferior in compression compactability and cannot be molded products having practically sufficient hardness under a commonly used compression pressure of 10-20 MPa.
As stated above, compactability, flowability and disintegration property are properties incompatible to each other in cellulose particles of the prior art and realization of a cellulose particle having all of these physical properties in a good balance have been desired.
In the meantime, since the cellulose particles described in Patent Documents 3-12 do not have intentionally formed pores within a particle and the volume of the pores within a particle is small, they can hardly carry an active ingredient within a particle and there were problems of liquid exudation at the time of compression shaping and troubles in tableting. On the other hand, the cellulose particles described in Patent Documents 1 and 2 have pores within a particle but due to small pore diameter they had a problem that water is hard to permeate into the dense and continuous cellulose wall and therefore they do not disintegrate in water and may cause problems for rapid release of the active ingredient.
In addition, since these cellulose particles do not have intentionally formed pores within a particle and the volume of the pores within a particle is small and they can hardly carry an active ingredient within a particle, they have shortcomings that they release the active ingredient so slowly that they cannot be practically used in a solid formulation of a poorly water-soluble active ingredient unless they are subjected to a complicated process comprising once granulating with water and/or an organic solvent followed by drying and that in the case of a solid formulation of a sublimating active ingredient, the active ingredient may be recrystallized during storage and deteriorates the commercial value.
An active ingredient in a solid formulation for internal application elutes from a drug into body fluid in digestive organs and the active ingredient is absorbed by digestive organs, enters to systemic circulation blood to show the drug efficacy. Because dissolution of poorly water-soluble active ingredient is low, it may be excreted before the administered active ingredient dissolves entirely and exhibits sufficient efficacy. The ratio of the amount of the entire active ingredient which enters the systemic circulation blood to the amount of the administered active ingredient is generally known as bioavailability. Various kinds of methods for improving the dissolution of poor solubility active ingredient have been examined conventionally aiming for improvement of the bioavailability and fast-acting of the active ingredient.
Patent Document 13 describes a method of co-pulverizing the poorly water-soluble active ingredient with β-1,4-glucan powder. Since the pulverizing treatment must be continued for an extended period of time until the crystallinity of β-1,4-glucan powder disappeared and strong shearing force must be continuously imposed for a long time with an abrasive roll mixer, this method had a problem that it is inefficient in the actual production. In addition, there was a problem that the β-1,4-glucan which lost crystallinity had a low compression compactability.
Patent Document 14 describes a method of blending β-1,4-glucan, a disintegrator and a surfactant for producing a solid preparation to be orally administered from a poorly water-soluble pharmacological agent by direct tableting method so as to enhance the strength and eliminate variation of the content of the principal agent and to promote degree of degradation of a tablet and dissolution rate of the principal agent. This publication did not mention about pores within a particle and it was not known at all to improve water-solubility of a pharmacological agent by blending a poorly water-soluble active ingredient with porous cellulose particles. In addition, it is needed to blend a surfactant in order to promote dissolution of a poorly water-soluble active ingredient and there remained a problem to be solved that inflammation was caused on the mucous membrane of digestive organs by the surfactant when the solid preparation was administered.
Patent Document 15 describes that when tablets are produced using a poorly water-soluble principal agent and β-1,4-glucan by wet tableting method going through the steps of powder mixing, kneading, granulating and drying, tablets having a high tablet hardness, a short disintegration time and a high dissolution rate of the principal agent are produced by adding a water-soluble polymer solution. This publication did not mention about porous cellulose particles having large pores within a particle and it was not known at all to improve water-solubility of a pharmacological agent by blending a poorly water-soluble active ingredient with porous cellulose particles. In addition, a number of steps relating to drying oil adsorbed materials are essential in such a process, and facilities cost incurred by the process and high energy cost for drying are problems to be solved. Furthermore, there were other problems to be solved such that the process cannot be applied to active ingredients which are deactivated by heat.
In addition, Patent Document 16 describes a method for improving dissolution of a pharmacological agent by mixing a poorly soluble pharmacological agent with cellulose particles with porous structure having a particular specific surface area and pore volume and allowing the former to be sublimated and adsorbed onto the latter which is obtained by dispersing particulate natural cellulose in an organic solvent and granulating and drying it by spray-dry method. The porous cellulose particles described in the document have a high specific surface area and a large pore volume and therefore improvement in dissolution is surely observed when the poorly water-soluble active ingredient is sublimated and adsorbed. However, there is a problem of storage stability in the Examples of this patent document, in which cellulose particles having an excessively high specific surface area are used and the active ingredient sublimated and adsorbed on the surface is amorphous, that the active ingredient partially crystallizes during storage which may change dissolution rate, etc. and further, they had shortcomings that a strongly-bonded molded product composition such as a tablet was hard to collapse due to poor disintegration property and the active ingredient was slow to be eluted.
Sublimable active ingredients have a problem that they exude from the solid preparation during storage and most of these solid preparations have been subjected to film coating or sugarcoating for the purpose of preventing the problem. However, even when such measures was taken, there remained problems that the active ingredient passes through the film layer and goes out of the product, which causes variation of the active ingredient in the preparation, adheres onto the surface of the preparation to cause irritating odor at the time of taking a drug, and recrystallizes within a storage container such as a bottle to significantly reduce the commercial value. In the case of an uncoated preparation, sublimation recrystallization becomes more remarkable compared with a coated preparation.
As already mentioned, since Patent Document 16 used cellulose particles having an excessively high specific surface area and the active ingredient sublimated and adsorbed on the surface thereof has become amorphous, there were problems that storage stability of active ingredient was poor and shortcomings that a strongly-bonded molded product composition such as a tablet was hard to collapse due to poor disintegration property and the active ingredient was slow to be eluted.
In addition, Patent Document 17 describes, as a method for preventing recrystallization of ibuprofen in a solid preparation due to sublimation, a method of storing an ibuprofen-containing solid preparation along with one or two or more stabilizing substances selected from the group consisting of polyvinylpyrrolidone, magnesium oxide and sodium hydrogen carbonate in a closed container such as a bottle. According to such a method, adhesion of crystals to a closed container during storage of the preparation and irritating odor of the preparation are surely alleviated, but it is necessary to put polyvinylpyrrolidone, magnesium oxide, sodium carbonate, etc. in the container as a different preparation, and the process becomes complicated. Therefore, this is utterly different from the preparation containing a sublimable active ingredient of the present invention which provides a single preparation in which sublimation is prevented by putting porous cellulose in the preparation.
Conventionally, a composition containing an active ingredient which is oily, liquid or semisolid at normal temperature causes oozing of a liquid ingredient from the preparation when compressed and shaped and therefore it is more likely to cause troubles in tableting in particular as compared with a solid active ingredient and also has problems of causing spots of the liquid ingredient on the surface of the resulted preparation, flowability defectiveness in the case of a granular preparation, and the like. These problems do not only reduce commercial value significantly but also cause variation of concentration and/or efficacy of the active ingredient and therefore improvement thereof is extremely important.
Patent Documents 18-29 describe a method of holding an active ingredient which is liquid or semisolid at normal temperature as it is onto the adsorbing carrier or holding an active ingredient which has been dissolved, emulsified or suspended in water, an organic solvent, oils and fats, a water-soluble polymer or a surfactant followed by a drying step and compressing and forming the resulted dry powder or granulated powder. However, the active ingredient which is liquid or semisolid at normal temperature may ooze at the time of compression and cause troubles in tableting and sufficiently compressed molded product may not be obtained. In addition, these Patent Documents do not mention about pore volume within a particle with regard to cellulose particles, and it has not been known at all that when the active ingredient which is liquid or semisolid at normal temperature is compressed, addition of porous cellulose aggregate having a large pore volume within a particle of the present invention will prevent oozing by holding the active ingredient which is liquid or semisolid at normal temperature within the particles of the porous cellulose aggregate and facilitate the production of a solid preparation such as powder, granulate and tablet. In addition, a number of steps relating to drying are essential in the processes of Patent Documents 18-29, and facilities cost incurred by the processes and high energy cost for drying are problems to be solved.
As a method of mixing crystalline cellulose and an active ingredient to enhance mixing homogeneity of the active ingredient and reduce the variation of active ingredient, Patent Document 30 discloses a method of mixing a pharmacological agent and talc, light quality silicic anhydride, silicon dioxide hydrate, stearate as a fluidizing agent followed by mixing the mixed powder with other additives in mixing of a pharmacological agent and additives and describes that crystalline cellulose is excellent in miscibility among additives other than the fluidizing agent. However, there was no description at all about pores within a particle of cellulose such as crystalline cellulose, and it has not been known that the mixing homogeneity of an active ingredient can be improved by blending porous cellulose aggregate particles to hold the active ingredient within the particles as in the present invention. This document also describes that the method is preferably applied to a highly aggregating pharmacological agent which is in the form of a fine powder having an average particle size of 40 μm or less to exhibit the effect significantly but the smallest particle size of the pharmacological agent actually described in the Examples of the document is 16 μm and as for the particles pulverized to 10 μm or less for the purpose of enhancing the dispersibility at the time of dosing a poorly water-soluble active ingredient, for example, aggregating properties of the active ingredient were markedly increased and there was a case where sufficient mixing homogeneity was not achieved for conventional crystalline cellulose in which the pore within a particle was small (Comparative Example 31 of the present invention).    [Patent Document 1]: JP-A-01-272643    [Patent Document 2]: JP-A-02-84401    [Patent Document 3]: JP-B-40-26274    [Patent Document 4]: JP-A-53-127553    [Patent Document 5]: JP-A-63-267731    [Patent Document 6]: JP-A-06-316535    [Patent Document 7]: JP-A-11-152233    [Patent Document 8]: WO02/02643    [Patent Document 9]: JP-A-04-283520    [Patent Document 10]: JP-A-07-173050    [Patent Document 11]: JP-A-07-507692    [Patent Document 12]: WO02/36168    [Patent Document 13]: JP-B-53-22138    [Patent Document 14]: JP-A-53-044617    [Patent Document 15]: JP-A-54-052718    [Patent Document 16]: JP-A-03-264537    [Patent Document 17]: JP-A-08-193027    [Patent Document 18]: JP-A-56-7713    [Patent Document 19]: JP-A-60-25919    [Patent Document 20]: JP-A-61-207341    [Patent Document 21]: JP-A-11-193229    [Patent Document 22]: JP-A-11-35487    [Patent Document 23]: JP-A-2000-16934    [Patent Document 24]: JP-A-2000-247869    [Patent Document 25]: JP-A-2001-181    [Patent Document 26]: JP-A-2001-316248    [Patent Document 27]: JP-A-2002-534455    [Patent Document 28]: JP-A-2003-161    [Patent Document 29]: JP-A-2003-55219    [Patent Document 30]: JP-A-2003-81876